Studies of mammalian germ cell development and meiosis

The Cohen lab has been instrumental in defining the role of the DNA mismatch repair (MMR) pathway in mammalian meiosis. Using mouse mutants for each of the mammalian MMR orthologs, we have determined that MSH4/MSH5 heterodimers recruit MLH1/MLiH3 to class I crossover sites in order to specify the appropriate number and spacing of crossover events in the mammalian genome.

Our continued research in this area focuses on how these crossover mediators of the class I pathway interact with mediators of the class II pathway, through recruitment and integration via key helicases and endonucleases such as BLM, EXO1, and SLX4. In addition, we are currently investigating the role of the cyclin n-terminal domain containing protein-1 (CNTD1) in controlling class I crossing over. For more details click on image.

Small RNAs are known to be important regulators of germ cell development, primarily through the action of the germline-specific PIWI-interacting, or piRNAs. Recently, our lab has explored the role of the Argonaute family of small RNA binding proteins, focussing specifically on the class of Argonautes that are specific to microRNA and endosiRNA species, but which do not interact with the piRNAs.

Our data demonstrate that AGO4 binds microRNAs in mammalian germ cells and that this interaction is important for numerous aspects of germ cell development, particularly in meiosis. Our continued studies in this area are aimed at understanding how AGO4 and its RNA binding partners mediate essential events during prophase I and beyond in the mouse. These studies formed the basis for our recently awarded U54 Center Grant, as part of the NICHD "Specialized Co-operative Centers Program in Reproduction". For more details click on image.

While studying proteins that may influence meiotic crossing over in the mouse, we became interested in the newest member of the Fanconi Anemia pathway, SLX4 or FANCP. SLX4 interacts with key components of the recombinogenic machinery in mammals and, as such, is well placed to regulate cross over pathways as described elsewhere in this website.

In addition to its role in meiotic recombination, we are also investigating the role of the Fanconi network as a whole, but FANCP/SLX4 more specifically, in germ cell development. Led by Dr. Kim Holloway, these studies are aimed at understanding the role of the FA network in germ cell proliferation
and genome maintenance in primordial germ cells. For more details click on image.

The extracellular signal regulated kinases, ERK1 and ERK2, play important roles in signaling downstream of hormones and growth factors. In ovarian cumulus cells, the ERKs are essential for mediating key events during folliculogenesis that ultimately facilitate ovulation. Studies in conjunction with the lab of Dr. Mark Roberson are ongoing to explore the role of the ERKs in meiotic prophase I and in events specifically within the oocyte of the adult ovary. For more details click on image.

The NIMA-like kinase, NEK1, is a member of a large family of serine threonine kinases that is unique amongst its family members in that it also encodes tyrosine kinase activity. We became interested in NEK1 when we discovered an important interaction between NEK1 and two SC components: SYCP1 and FKBP6. More recently we have identified a key role for NEK1 in removal of key cohesin components at the end of prophase I in mouse spermatocytes (Holloway et al, 2011). Studies are ongoing to identify the exact molecular mechanisms by which NEK1 participates in these events.

IN THE NEWS ....

The Cohen lab says farewell and good luck to Kim !

We are proud to congratulate Dr. Kim Holloway on her new position as Grants and Contracts Officer at Cornell University. Though she is not officially in the lab any more, we are all happy that sheremains close by and she will always hold anhonarary position in the Cohen lab. We know she will do a fabulous job in The Office of Sponsored Programs!

Congratulations to Steve !

Congratulations to Dr. Stephen Gray on the publication of his recent manuscript in Nature. In work performed as part of his PhD, Steve contributed to an exciting study focussing on the role of the Tel1

(ATM) kinase in the placement of crossover sites budding yeast. This exciting paper shows Tel1 is important for the localized restriction of closely-spaced crossover events ("interference"). See January 2015 of Nature.

The role of CNTD1 in mammalian meiosis

We are proud to announce our new publication in the Journal of Cell Biology focussing on the role of Cyclin N-Terminal Domain-containing protein-1 (CNTD1) in crossover designation. This was a collaboration with our good friend, Dr. Anne Villeneuve, from Stanford University. We demonstrate that CNTD1 is crucial for paring down excess DSB repair sites during pachynema of prophase I, in conjunction with HEI10. The paper was highlighted by an In Focus report in the same issue of the Journal. See our publications page for further details.

New Center grant for the Center for Reprogenomics

We are happy to report the success of our recent P50 application for a grant to study the role of small RNAs in mammalian gametogenesis. This Center grant encompasses projects from the Cohen, Grimson, Schimenti, and Paduch labs, and is funded by the National Institute of Child Health and Development. Funding started in April 2014.